Accessing three-dimensional molecular diversity through benzylic C-H cross-coupling

Abstract

Pharmaceutical and agrochemical discovery efforts rely on robust methods for chemical synthesis that rapidly access diverse molecules^1,2. Cross-coupling reactions are the most widely used synthetic methods³, but these methods typically form bonds to C(sp²)-hybridized carbon atoms (e.g., amide coupling, biaryl coupling) and lead to a prevalence of "flat" molecular structures with suboptimal physicochemical and topological properties⁴. Benzylic C(sp³)-H cross-coupling methods offer an appealing strategy to address this limitation by directly forming bonds to C(sp³)-hybridized carbon atoms, and emerging methods exhibit synthetic versatility that rivals conventional cross-coupling methods to access products with drug-like properties. Here, we use a virtual library of >350,000 benzylic ethers and ureas derived from benzylic C-H cross-coupling to test the widely held view that coupling at C(sp³)-hybridized carbon atoms affords products with improved three-dimensionality. The results show that the conformational rigidity of the benzylic scaffold strongly influences the product dimensionality. Products derived from flexible scaffolds often exhibit little or no improvement in three-dimensionality, unless they adopt higher energy conformations. This outcome introduces an important consideration when designing routes to topologically diverse molecular libraries. The concepts elaborated herein are validated experimentally through an informatics-guided synthesis of selected targets and the use of high-throughput experimentation to prepare a library of three-dimensional products that are broadly distributed across drug-like chemical space.

Fig. 1.. Benzylic C–H cross coupling reactions provide access to 3D chemical space.

a, Known bioactive compounds are topologically diverse, including planar structures like flurbiprofen (1) and 3D structures like JHW-007 (2). b, PMI of 1 and 2 with reference to selected bioactive molecules. c, Benzylic C(sp³)–H cross coupling reactions offer opportunities to introduce more three-dimensionality in contrast to C(sp²)-focused functionalization methods. Compounds 3 and 4 were visualized with force-field minimized conformations (see Methods for details).

Fig. 2.. Enumeration of P01-P20 and topological comparison between P01-P20 and CIC.

a, Display of selected benzylic C(sp³)–H scaffolds for cross coupling product enumeration. b, Enumeration of P01-P20 via etherification with alcohols and isocyanation/urea formation sequence with amines. c, Comparison of 3D scores between CIC and P01-P20 compounds by parent scaffold. See Methods for details of box-whisker plots in panel c. 3D^Avg, average 3D scores; 3D^Scaffold, the 3D scores of the benzylic C–H scaffolds A01–A20.

Fig. 3.

Analysis of functionalization products and structural derivatives of A11. a, Comparison of PMI and 3D scores between sp² and sp³ functionalization products derived from A11. b, Conformational study of selected sp², sp³ and sp³-acyclic ethers and ureas derived from A11. See Methods for details of box-whisker plots in panels a and b. 3D^Avg, average 3D scores; 3D^Min, 3D scores of minimum-energy conformer of a given compound.

Fig. 4.. Principal components analysis (PCA) comparing the physicochemical features of CIC and P01-P20 compounds.

a,b - Physicochemical features reflecting PC1 and PC2. c,d - Physicochemical features reflecting PC3 and PC4. Libraries are visualized in density heatmaps, where CIC (n = 9,425) and P01-P20 (n = 368,948) compounds were analyzed by 100 × 100 bins, and the color of each bin was determined by the number of compounds contained therein. Selected pairs of CIC and P01-P20 compounds with similar coordinates are showcased to highlight the higher 3D scores accessible with the P01-P20 compounds.

Fig. 5.. Synthesis of medicinally relevant benzylic C–H cross coupling products and comparison with bioactive molecules.

a, Assessment of benzylic ethers and ureas that sample the chemical space generated from virtual enumeration. b, Comparison of selected P01-P20 products (including all isolated regio- and stereoisomers) with CIC space in PCA, PMI and Box-Whisker (3D scores) plots. ^aReaction run with 15 mol % CuCl/biox. ^bReaction run at room temperature. ^cReaction run with 20 mol % CuCl/biox. ^dReaction run at 30°C. ^eReaction run in DCM. ^fIsocyanation reaction run at 40°C. ^gIsocyanation reaction run at room temperature.

Fig. 6.. High-throughput synthesis of medicinally relevant benzylic C–H cross coupling products.

a, Parallel synthesis of 48 benzylic ethers and 48 benzylic ureas via cross coupling of 4 benzylic C–H scaffolds and 12 alcohols and 12 amines respectively. Reaction conditions were the same as described in Fig. 5a. b. Display of reaction outcomes of the 96 benzylic C–H cross coupling reactions monitored by HPLC-MS. Products were found in 70 reactions out of 96 substrate pairs, with 21 of which were selected for purification. Benzylic regioisomers for some products were also observed (see Supplementary Information for details)